DESCRIPTION(provided by applicant): Sarcopenia, the aging-associated loss of muscle mass and function, is an important public health problem that contributes to frailty, decreased functional mobility, increased risk of falls and fractures, and a poor quality of life. The primary objective of the proposed competing continuation application is to determine whether testosterone replacement of older men who have low testosterone levels and are at increased risk for disability because of the presence of sarcopenia will increase their maximal voluntary muscle strength of major upper and lower extremity muscle groups. The second objective is to determine whether testosterone replacement will improve muscle power, performance in standardized, measures of physical function, reaction time, balance, and physical activity, and reduce the risk of disability. The third objective is to determine whether testosterone supplementation improves fatigue, affectivity, and overall sense of well being in older men with sarcopenia and low testosterone level. We will conduct a randomized, placebo-controlled, parallel group, double-blind trial in which 252 medically stable, older men, 65-85 years of age with total testosterone <350 ng/dL and/or free testosterone <50 pg/ml by dialysis, and sarcopenia will be randomized to receive either testosterone (10 g) or placebo gel daily for six months. Sarcopenia will be operationally defined by DEXA scanning as appendicular lean soft tissue mass that is two standard deviations below that for healthy, young men (<19.6 kg). The 10 g daily dose of testosterone gel is expected to increase serum testosterone concentrations into the mid- to high-normal range (-600-700 ng/dL). Maximal voluntary strength in the leg press, chest press, leg curls, and lastissimus pull exercises, leg power, performance in several measures of physical function (Margaria power test, walking speed, load carry, and reach and lift test), reaction time, static and dynamic balance, and self-reported disability will be assessed before, during and after 6-months of treatment. The effects of testosterone on fatigue by Chalder Fatigue Scale, affectivity by DeRogatis Affectivity Balance Scale, and sense of well being by Psychological Wellbeing Index will be assessed before, during and after treatment. For safety, we will monitor blood counts and chemistries, PSA, prostate examination, AUA/IPSS symptom score, sleep apnea, and local skin reactions. Careful subject selection, optimization of testosterone dose, the use of an objective operational definition of sarcopenia and measures of muscle performance that are important for functional activities and have been shown to be androgen-responsive, attention to effect size and power considerations, and a multi-disciplinary team of investigators will maximize the chances of finding a treatment effect, if any. The study will provide unique information about the effectiveness of a rational, but hitherto unproven therapeutic strategy, for older men with sarcopenia who are at increased risk of disability.